Radiobiology and targeted therapy

The full text of the publication follows. Most of what is known in radiobiology of radiation therapy has been determined in experiments using conventional external beam radiotherapy (CEBR). However, targeted radiotherapy and radioimmunotherapy (RIT) in particular, differ in many ways from CEBR. First, while CEBR mostly use energetic photons, RIT relies on the use of vectors specifically directed against tumor cells or their microenvironment, and labeled with radioisotopes. Radioisotopes may decay by emitting helium nuclei, energetic or non energetic electrons, that may be associated or not to X or γ-rays. The path length in biological materials of the emitted particles ranges from few nm to several mm and is straightly correlated with energy and linear energy transfer (LET). Finally, targeted cell may be exposed to self- and cross-fire irradiation and to both low- and high-LET radiation. These physical characteristics make that highly heterogeneous doses are delivered at the cellular level or at the level of the tumor burden. Therefore, the correlation between the biological endpoints and the absorbed irradiation dose must be investigated carefully and sophisticated dosimetric approaches are required. RIT is also featured by extended exposure delivered at very low dose rate (LDR) (<1 Gy/h vs 60 Gy/h for CEBR) and declining progressively. Such a LDR provides a window of opportunity for the cell to repair radiation-induced damage and to proliferate. However, experimental data showed that tumor cells are more sensitive to LDR than to HDR for final equivalent irradiation doses. Cell death might involve mostly apoptosis for hematological malignancies and mitotic death for solid tumors. Death would be due to a single hit killing phenomenon and might involve G2/M cell cycle arrest. Since bystander effect is essentially a low dose phenomenon observed after CEBR, it plays a significant role in RIT. Therefore, it might compensate for heterogeneous distribution of radiolabeled vectors within tumor burden and could be complementary to cross-fire irradiation in producing additional cell kill. (author)